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Mathematics in Molecular Biology and Medicine
D. Sumners
Two major scientific revolutions began in the mid-twentieth
century, one in computation/information processing and one
in molecular biology. Spurred by wartime computational needs
at Los Alamos, the electronic computer was born. A decade
later at the Cavendish Laboratory in Cambridge, the landmark
discovery of the DNA double helix was the key that opened
the door and signaled the beginning of the revolution in molecular
biology. In the fifty years since then, exciting scientific
breakthroughs in both areas have been made at a mind-numbing
rate. On the one hand we have relatively enormous and cheap
computing power, and on the other we have the sequencing of
the complete human genome. In terms of prospects for future
progress, molecular biology is positioned at the beginning
of the twenty-first century where physics was at the beginning
of the twentieth century. Biology enjoys exquisite experimental
ability and control, teasing out ever-deeper secrets. Simultaneously,
computerized instrumentation and automation of experimental
processes allow acquisition of biological data at an exponentially
increasing rate. Biology now stands poised to climb the mountain
of the understanding of life. Success of this climb depends
on the increasing involvement of mathematics. Biology needs
a great and immediate increase in the number of mathematicians
inspired by biological problems, and a corresponding increase
in the number of biologists appreciative of the potential
for mathematical and computational techniques to spur scientific
progress. Mother Nature does not give up her secrets easily;
data does not come with instructions. Mathematics builds models
which connect sparse data points with threads of logical argument,
weaving these logical threads together to produce a fabric
of understanding. Computation based on theory is essential
in filling in gaps in understanding, extending the ability
of the human mind to organize and comprehend the massive biological
datasets now being produced. In order to drink from this firehose
of biological data and convert some of it into knowledge,
mathematics and computation (both old and new) are needed
to build models and navigational tools.
The scientific heir apparent for the rapid increase in knowledge
in molecular biology is medicine. The human body is an extremely
complicated biological system. A goal now being formulated
in research medicine is the complete human in silico. This
dream is to generate interoperable computational models for
human biology spanning all scales, from molecular to cellular
to organs to organ systems. Access to such models would, for
example, greatly enhance rational drug design, allowing computational
testing of hypothetical drugs. It would greatly enhance understanding
of "normal" function in human biological systems and the non-invasive
diagnosis of disease states, using computational comparison
of subject anatomy and function to template anatomy and function.
Mathematics has maximal impact on molecular/cellular biology
and medicine via the feedback loop of interaction: mathematical
models are built in response to unsolved problems and experimental/clinical
results; the theory is converted into algorithms for machine
computation; computations and theory are used to make predictions
and analyze experimental data; results of this analysis are
used to refine the theory and computation.
As an example of impact of mathematics on biology, consider
the spectacular recent advances in computational genomics.
The process of sequencing the 3 billion base pair human genome
is achieved through sequencing hundreds of thousands of smaller
randomly overlapping contiguous genetic segments. In order
to arrange these segments in the biologically correct linear
order, one must compute the overlap probability among segments.
After one has assembled the bits of the genome and has the
correct linear sequence, one must then find the genes, the
short, scattered regions of DNA which code for currently unknown
proteins. This is a mathematical problem of pattern recognition
and biological cryptology, using every mathematical trick
in the book and some yet to be invented. The mathematical
nature of this task is the reason why every drug company in
the world is hiring mathematicians and computer scientists,
generating very stiff competition for mathematicians fluent
in biology. After one has the DNA sequence for a gene, and
hence the amino acid sequence for the encoded protein, one
must then compute the three-dimensional structure (native
fold) for the protein, and from this structure, (hopefully)
deduce function. Current attempts at solving the well-known
protein-folding problem rely on ab initio mathematical modeling
and computation, and bootstrapping using annotated protein
databases. After finding the 3D protein structure (or perhaps
avoiding this step entirely), one must then find the function
of the protein. For this, one uses 3D information, bootstrapping
via database comparison of sequence and structure information
with proteins of known sequence, structure and function, microarray
chip technology which tells one that the gene which encodes
the unknown protein is active or inactive in concert with
genes that encode proteins of known structure and function,
experiments based on geometric and topological assays for
mechanism, etc. Determining structure and function of proteins
is difficult, and this new science has been termed proteomics.
Proteins rarely act alone; they act in concert with numerous
other proteins. Understanding how proteins "talk" to each
other and elucidating the cascade of regulation and function
of proteins in the cell is the next hurdle. In every step
of this climb of discovery, mathematics/computation has been
and will be a major player.
One role of mathematics in medicine at the microscopic level
is to "peer behind the curtain," using mathematics to compute
the structure and function of life-sustaining enzymes that
operate on DNA. The same enzymes that sustain life are also
involved in life-threatening diseases, such as cancer; understanding
structure and function opens the door to therapy. Microarray
chip technology will soon permit disease treatment chemotherapy
protocols to be tailor-made for the individual patient. The
mathematics for microarray chip design and data analysis is
now under intense development. At the macroscopic level, a
fundamental problem in medicine is to understand and define
"normal" anatomy and function for an organ. Due to high variability,
comparison of anatomical and functional information across
individuals and across groups of individuals requires sophisticated
mathematical models. Mathematics can elucidate the function
of vital organs, such as the heart and the brain. In the heart,
detailed knowledge of heart geometry and muscle fiber orientation
can be used to build sophisticated models, where the onset
of fibrillation can be studied. Mathematicians are using these
sophisticated models to design better defibrillators. In the
brain, mathematics is useful in relating brain architecture
(as revealed by high-resolution MRI scans) to brain function
(as revealed by Positron Emission Tomography (PET) and functional
Magnetic Resonance Imaging (fMRI) scans). For example, one
can use a modern realization of a 150-year-old theorem (the
Riemann Mapping Theorem) to produce unique conformal flattenings
of the surface of the brain, helping scientists to use canonical
surface-based coordinate systems to compare brain function
across individuals.
In summary, mathematics has been and will always be a major
player in the team effort to understand the complexities of
molecular biology and to harness this understanding to enhance
human health.
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